The active metabolite of vitamin D, 1,25-(OH)2-D3, is a well known modulator of calcium homeostasis in man. In recent years, the discovery of specific 1,25-(OH)2-D3 receptors on a variety of malignant and non-malignant cells has prompted an investigation of the potential effect of the hormone on these cells. The presence of such receptors on activated human lymphocytes led us to the following observations. When peripheral human mononuclear cells were activated with lectins or antigen in vitro, a dose-dependent inhibition of DNA synthesis was observed in cells incubated with 1,25-(OH)2-D3 in concentrations ranging from 10-10 to 10-7 M. Production of IgG and IgM, determined by enzyme-linked immunosorbent assay, was similarly inhibited by increasing concentrations of the hormone. Further studies examining lymphocyte subsets revealed the T helper cell (TH) to be the specific cellular target for the immunoinhibitory effect of 1,25- (OH)2-D3. In two T cell dependent animal models of autoimmunity, experimental allergic encephalomyelitis (EAE) and murine interstitial nephritis, specific T cell clones of the helper phenotype can be isolated and shown to exert biological activities in vitro and in vivo. In humans, T cell clones can be generated from lymphocytes of rejected allografts with HLA-DR specificities. In light of these findings, we propose to further evaluate the immunoregulation role of 1,25-(OH)2-D3 by assessing (1) the ability of 1,25-(OH)2-D3 to interfere with the properties and functional characteristics of the T cell clones: proliferation, lymphokine production, helper or suppressor function, transfer of disease activity and delayed-type hypersensitivity and (2) the ability of 1,25-(OH)2-D3 treated murine recipients to be protected from the active induction of EAE and murine interstitial nephritis or from the passive transfer of the autoimmune diseases by T cell clones. We believe this work will advance our understanding of cellular and humoral mechanisms affected by the active vitamin D metabolite, a potential immunosuppressive agent.